Chikungunya virus (CHIKV), an emerging, mosquito-borne alphavirus and potential biological weapon that has caused debilitating and often chronic arthralgia in at least 2 million persons during the past 2 years, was recently placed on the NIAID list of priority pathogens as a recognition of its emergence potential. Due to difficulties with clinical diagnosis, CHIKV is grossly underreported and probably causes far more disease than is recognized in Africa and Asia, including occasional fatalities. Like dengue virus, CHIKV uses humans as amplifying hosts and therefore can disseminate readily in travelers, suggesting that it will eventually become established the Americas. There are no licensed vaccines or effective therapies, and the only vaccine strain tested in humans is reactogenic. We will capitalize on our recent successes with chimeric alphaviruses to develop novel CHIKV vaccine candidates that are superior to traditionally derived, cell culture-passaged mutants. Using genetic backbones derived from 3 relatively avirulent alphavirus strains, and structural protein genes from CHIKV, we will generate and optimize chimeric cDNA clones to produce candidate vaccine strains that replicate efficiently in Vero cells, and are highly attenuated yet rapidly immunogenic and efficacious in preventing CHIK disease. Several vaccine candidates will be evaluated for attenuation and efficacy in a murine model, and the most promising strains will then be tested extensively in mice for immunogenicity and efficacy in preventing disease, viremia and mortality. Vaccine constructs with the best efficacy will be evaluated for safety using neurovirulence and SCID mice testing. Vaccine formulations will be identified to optimize thermal stability, long-term storage and ease of distribution. The resulting product will dramatically improve U.S. preparedness for this important emerging virus, as well as provide the first effective vaccine for an important emerging infectious disease. PUBLIC HEALTH RELEVANCE: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has emerged on islands off the east cost of Africa, spread to the Indian subcontinent and recently to Italy, affecting over 2 million persons during the past 2 years. CHIKV is also a potential biological weapon and was recently added to the NIAID priority pathogen biodefense list. A safe, effective chimeric Chikungunya vaccine would improve public health worldwide and would be an important asset to our biodefense portfolio.